This invention relates to pharmaceutical compositions comprising tin-117m (Sn-117m) stannic complexes in a defined dose range and methods of using said compositions to alleviate bone pain and to treat osseous metastatic disease.
The preparation of tin-117m-labeled stannic (Sn4+) chelates which localize to bone, and their use as diagnostic radiopharmaceuticals, is described by Srivastava et al., U.S. Pat. No. 4,533,541 (Reference 1) which is incorporated herein by reference. In addition to a description of preparation of Sn-117m stannic complexes of methylene diphosphonate (MDP), pyrophosphate (PYP), ethylidenehydroxydisodium phosphonate (EHDP), and diethylenetriaminepentaacetic acid (DTPA), Srivastava et al. describe the preferential localization of Sn-117m stannic complexes in bone to the substantial exclusion of uptake by blood, muscle, kidney, or liver. (Reference 2.) Autoradiographic studies have shown that the Sn-117m stannic complexes localize to cortical bone but not bone marrow. (Reference 3.) There is no indication, however, of a composition or treatment with Sn-117m stannic complexes to alleviate pain associated with cancer in human skeletal bone, or to treat cancer in human skeletal bone.
Cancer of the bone and osseous metastases derived from tumors elsewhere (e.g. prostate, breast, and other cancers) can result in substantial pain. The alleviation of such bone pain is highly desirable. A number of radiopharmaceutical agents have been used for the palliation of bone pain from metastatic lesions, primarily originating in breast and prostate cancers. Among these are phosphorus-32 (Reference 4), strontium-89 chloride (Reference 5), samarium-153 EDTMP (Reference 6), rhenium-186 HEDP (Reference 7), and iodine-131 hydroxybenzylidene diphosphonate (HBDP) (Reference 8). One of these, strontium-89 chloride, was approved by the FDA for commercial distribution in June, 1993. Treatment with known radiopharmaceutical agents is limited because of undesirable side effects resulting from uncontrolled irradiation. For example, a limiting factor has been amount of radiation absorbed by red marrow. This results from a lower than desired bone tumor to bone marrow ratio which causes bone marrow toxicity at therapeutic dosages.
Results have been reported of a study in which whole-body distribution of Sn-117m (Sn4+) DTPA was observed to obtain absorbed dose estimates. (Reference 9.) There was no indication in this article of actual treatment or composition effective to relieve pain and treat cancer in human skeletal bone.
Generally, the use of internally administered radiotherapeutic compositions can result in significant toxicity due to destruction of non-cancerous tissues, such as bone marrow. It would, therefore, be advantageous to be able to utilize a radiopharmaceutical composition and a treatment which produce minimal toxicity, but provide highly effective, reproducible results.
The present invention provides pharmaceutical compositions for therapeutic applications, including bone pain palliation and radiotherapy, which comprise Sn-117m stannic tin chelate complexes (chelates) which localize to bone and which are provided in a specific method of treatment, e.g., dose range of radioactivity as well as composition. The present invention also provides methods for using said Sn-117m complexes to provide alleviation or palliation of bone pain and for treatment of bone cancer.
The invention provides pharmaceutical compositions which include chelate complexes of Sn-117m tin (Sn4+). Preferred chelating agents include the ligands methylenediphosphonate (MDP), pyrophosphate (PYP), ethylidenehydroxydisodium phosphonate (EHDP), diethylenetriaminepentaacetic acid (DTPA), and mixtures thereof. Most preferably, the compositions include Sn-117m (Sn4+) DTPA, in the dose range of from between about 6 mCi and about 50 mCi per 70 kg of body weight. The compositions also include a pharmaceutically acceptable carrier.
Preferably, the compositions of the invention also include a toxicity control agent which reduces and/or eliminates toxicity resulting from the chelating agent. Such toxicity control agents include, for example, sources of calcium sufficient to prevent hypocalcemia, which can be induced by chelating agents introduced into blood. Preferably the source of calcium is calcium chloride.
The Sn-117m stannic chelate complexes preferably are prepared using Sn-117m of a specific activity of at least about 2 mCi/mg, preferably from about 2 mCi/mg to about 100 Ci/mg, more preferably from about 2 mCi/mg to about 50 Ci/mg.
According to the method of the invention, the dosage of the Sn-117m-containing composition may be between about 6 mCi and about 50 mCi per 70 kg of body weight. Preferably, the dosage is between about 8 mCi and about 30 mCi per 70 kg of body weight. More preferably, the dosage is between about 9 mCi and about 25 mCi per 70 kg of body weight, and most preferably, between about 12 mCi and about 20 mCi per 70 kg of body weight.
As a result of the invention, the excruciating pain associated with cancer in human skeletal bone has been dramatically reduced by treatment with an agent which selectively attacks the source of the pain. Consequently, the treating physician is armed with an effective pain-management tool which is substantially less debilitating to the quality of the patient""s life than total sedation. As a further consequence, the use of addictive drugs is significantly reduced.
It has also been found, surprisingly and unexpectedly, that the present invention provides a unique method of treatment and specific compositions using Sn-117m complexes which are highly effective in treating cancer in human skeletal bone whilst eliciting no significant or minimal toxicity. These advantages have been realized by discovering a unique pharmaceutical composition of this invention, and the results found herein have not been observed with treatments and/or compositions outside the parameters of the present invention.
These and other advantages of the present invention will be appreciated from the detailed description and examples which are set forth herein. The detailed description and examples enhance the understanding of the invention, but are not intended to limit the scope of the invention.